Claims for Patent: 10,590,102

Summary for Patent: 10,590,102

Title:	Crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]methanone
Abstract:	This disclosure relates to the crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone. The disclosure also relates to pharmaceutical compositions comprising the crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone. The disclosure also relates to methods of treating cancers comprising administering to a patient in need thereof the crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone.
Inventor(s):	Brown; Adrian St. Clair (Ely, GB)
Assignee:	EXELIXIS, INC. (Alameda, CA)
Application Number:	15/852,280
Patent Claims:	1. A crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone having the formula: ##STR00013## wherein the crystalline fumarate salt is designated as Form A. 2. The crystalline fumarate salt of claim 1, characterized by at least one of the following: (i) a .sup.1H NMR spectrum in d.sub.6 DMSO substantially as depicted in FIG. 2; (ii) a .sup.13C NMR spectrum in d.sub.6 DMSO substantially as depicted in FIG. 3; (iii) a solid state .sup.13C NMR spectrum with three or more peaks selected from 175.3, 173.6, 117.5, 155.5, and 153.5, .+-.0.2 ppm; (iv) a solid state .sup.13C NMR spectrum substantially as depicted in FIG. 4; (v) a powder x-ray diffraction pattern (CuK.alpha..lamda.=1.5418 .ANG.) comprising three or more 2.theta. values selected from 4.6, 12.1, 13.2, 13.6 and 14.5 .+-.0.2 .degree.2.theta., wherein measurement of the crystalline form is at room temperature; (vi) an x-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG. 10; and (vii) a differential scanning calorimetry thermogram substantially in accordance with FIG. 8. 3. A crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone, designated as Form A, wherein said salt is characterized by a solid state .sup.13C NMR spectrum having three or more peaks selected from 175.3, 173.6, 117.5, 155.5, and 153.5, .+-.0.2 ppm. 4. A crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone, designated as Form A, wherein said salt is characterized by a powder x-ray diffraction pattern (CuK.alpha..lamda.=1.5418 .ANG.) comprising three or more 2.theta. values selected from 4.6, 12.1, 13.2, 13.6 and 14.5.+-.0.2.degree.2.theta., wherein measurement of the crystalline fumarate salt is at room temperature. 5. A crystalline fumarate salt of (S)[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-l-yl]-methanone of, wherein said salt is at least 90 weight % Form A. 6. A pharmaceutical composition comprising a crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-l-yl]-methanone, designated as Form A; and a pharmaceutically acceptable excipient. 7. A method of treating BRAF V600 mutant melanoma in a subject, the method comprising administering to the subject in need of the treatment a therapeutically effective amount of a crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone alone or in combination with vemurafenib. 8. The method of claim 7, wherein the administering of the crystalline fumarate salt of (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone takes place prior or subsequent to, or concurrent with vemurafenib. 9. A process for preparing a crystalline fumarate salt of Compound I designated as Form A, comprising: adding fumaric acid dissolved in a solvent to a mixture of Compound I dissolved in a solvent to form the crystalline fumarate salt of Compound I designated as Form A; and collecting the resulting crystals of the crystalline fumarate salt of Compound I designated as Form A; wherein Compund I is (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl]-methanone.